Autonomic Neuroscience: Basic and Clinical 181 (2014) 90–93
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Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Short communication
Reappearance of sympathetic skin response below a thoracic level-9 complete spinal cord injury Hatice Kumru a,b,c,⁎, Martin Schubert d, Jesus Benito a,b,c, Eloy Opisso a,b,c, Joan Vidal a,b,c a
Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la UAB, 08916 Badalona, Barcelona, Spain Univ Autonoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Barcelona, Spain d Spinal Cord Injury Center, University Hospital Balgrist, Forchstrasse 340, 8008 Zurich, Switzerland b c
a r t i c l e
i n f o
Article history: Received 23 July 2013 Received in revised form 24 October 2013 Accepted 29 November 2013 Keywords: Sympathetic skin response Complete SCI Below lesion
a b s t r a c t Reappearance of sympathetic skin response (SSR) below lesion is reported in a patient with a complete thoracic-9 spinal cord injury 6 months following injury. SSR was elicited by electrical stimulation of supraorbital nerve (SON) and pudendal nerve (PN). SON stimulation induced SSRs only in the hand. SSRs were initially absent below the level of SCI but reappeared only with PN stimulation. This case suggests that 6 months following a complete lesion, the isolated spinal cord can generate a SSR. Possible underlying mechanisms and implications for autonomic plasticity below spinal lesion are discussed in view of the literature. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Sympathetic skin response (SSR) is a simple, non-invasive electrophysiological test that examines the common efferent pathways of the sympathetic nervous system (Veciana et al., 2007; Vetrugno et al., 2003). Centers of the cerebral cortex and the brainstem have been proposed as sites where sensory signals generate the SSR (Korpelainen et al., 1993; Vetrugno et al., 2003). The recording of SSR allows an independent and objective assessment of disconnection of the sympathetic spinal centers from supraspinal control, which has been related with autonomic dysfunction in lesion levels above T6 (Curt et al., 1997). Except in one study where reproducible SSRs had been shown below a complete SCI elicited by pudendal nerve stimulation (Reitz et al., 2002) in seven subjects, no further evidence was found to support the hypothesis that the spinal cord isolated from the brain stem could generate a SSR (Cariga et al., 2002; Kumru et al., 2009; Nicotra et al., 2005a,b; Previnaire et al., 2012). Here, we describe the reappearance and reproducibility of SSR below the spinal lesion level at different time points of neurophysiological evaluations, following SCI from subacute until chronic phase and its relation with detrusor overactivity. The case reported here was observed within a clinical trial: ‘Effectiveness of a treatment of neurogenic detrusor overactivity by application of early external pudendal nerve stimulation’ performed
⁎ Corresponding author at: Hospital de Neurorehabilitació Institut Guttmann, Camí Can Ruti s/n. Barcelona, 08916 Barcelona, Spain. Tel.: +34 93 497 77 00; fax: +34 93 497 77 15. E-mail address: [email protected] (H. Kumru). 1566-0702/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autneu.2013.11.003
within the European multi-center study about SCI (see www.emsci.org). SSR was repeatedly assessed to evaluate effects on autonomic neuroplasticity. 2. Methods A twenty-four-year-old male patient suffered a complete SCI, with a spinal cord transection, due to a traffic accident three days prior to admission at our institution. On admission, initial neurological examination revealed sensory and motor complete SCI at the thoracic (T) 9. 2.1. Neurophysiological studies We performed electrophysiological studies with the patient supine (with ambient temperature: 22–24°). Patient underwent a neurophysiological evaluation (see www.emsci.org) for motor evoked potentials (MEPs), somatosensory evoked potential (SSEP) recordings and SSR. A Medelec synergy electromyograph (Oxford Instruments, England) was used for all the tests. MEPs were elicited by single transcranial magnetic stimulus using a Magstim Super Rapid (Magstim Company, Whitland, UK) through a double-cone coil over the vertex. MEPs were recorded by surface electrodes over tibialis anterior and adductor hallucis muscles bilaterally. Single sweeps of 100 ms were recorded, filtered at 10–2000 Hz and amplified with a gain of 0.1 mV/div. For somato-sensory evoked potentials (SSEPs), the tibial nerve and the pudendal nerve (PN) were stimulated. For PN SSEPs, the stimulation was applied with ring electrode over penis (cathode on penis, anode
H. Kumru et al. / Autonomic Neuroscience: Basic and Clinical 181 (2014) 90–93
2–3 cm further distal) (with 100 mA intensity and 0.5 ms duration). Two sets of responses were averaged with sweeps of 100 ms, filters set at 10 and 2000 Hz, and amplified at a gain of 2 μV/div. MEPs and SSEPs were recorded after 15 days and after 1 year following SCI to verify completeness of injury of somatosensory afferents and efferents. SSRs were recorded on the right hand, the right and left feet, and the perineum. For the hand, the active electrode was attached to the palm and the reference electrode to the dorsum. For the foot, the active electrode was attached to the sole and the reference to the dorsum. For perineum recordings, the active electrode was attached to the perineum (below the scrotum) and the reference electrode to the iliac crest with the ground on the right leg. For all SSR recordings, we used a band-pass of 0.1 to 100 Hz and a sensitivity of 0.5 mV per division. Sweep duration was 10 s. For stimulation above SCI lesion level, electrical stimulus was applied to the right supraorbital nerve (SON), and below SCI lesion level the pudendal nerve (PN) was stimulated. Duration of electrical stimulus of SON was 0.5 ms and the intensity was set at 15 mA to induce a clear SSR. For PN stimulation, we used a ring electrode over the penis (cathode proximal, anode 2–3 cm distal) (with 100 mA intensity and 0.5ms duration). Each stimulus was repeated at least 3 times at each point with an interstimulus interval at least 30 s to reduce habituation (Chroni et al., 2006; Kumru et al., 2009). Urodynamic testing: Cystomanometry (CMG) and ice water test (IWT) were performed subsequently (Abrams et al., 2003). SSR and urodynamic recordings were obtained in independent sessions around 15 days (just SSRs) and 1, 3, 6 and 10 months following SCI. 2.2. Data analysis MEPs and SSEPs were evaluated visually at highest resolution, and latency and amplitude were calculated if there was any response. We calculated the onset latency of SSR in the hand, the feet and in the perineum. SSR was considered present if the amplitude of SSR was ≥50μV and amplitudes were determined peak to peak. If there was no identifiable SSR, response amplitude was considered “0” and no value was entered for response latency. The SSR probability (%) to the total number of stimuli (n = 3) was calculated for each stimulated nerve. We used one-way ANOVA to compare latencies of SSR in feet and perineum. 3. Results The patient completed neurophysiological studies without any complaints at all time points. He did not present any symptoms of autonomic dysreflexia such as sweating, change of skin color, or blood pressure, spontaneously or during any of the neurophysiological examinations. During PN stimulation, he did not report any sensation (complete SCI). The clinical diagnosis of complete SCI at T9 was confirmed one year following SCI, clinically and by neurophysiological evaluation. After 15 days and 1 year following SCI, MEPs were absent in the studied muscles on both sides and SSEPs also were absent with TN stimulation from both sides and with PN stimulation. Popliteal fossa potentials with TN stimulation were always normal. The SON stimulation induced SSRs only in the hand without any SSRs in the feet, or in the perineum, at any time of evaluation following SCI (Fig. 1A, Tables 1–2). PN stimulation did not induce SSRs in any of the recorded areas (right hand, feet and perineum) after 15 days, 1 and 3 months following SCI (Fig. 1B, Table 1). However, after 6 and 10 months following SCI, SSRs reappeared with PN stimulation in the feet and perineum, but not in the right hand (Table 1, Fig. 1B). The latencies of SSR in the feet and the perineum were not significantly different (p N 0.2).
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The SON stimulation induced SSRs in the hand with 100% persistency, without any SSRs in the feet, or in the perineum, at any time of evaluation following SCI (Fig. 1A). The PN stimulation induced SSRs in the feet and perineum with 100% of persistency after 6 months following SCI, but not in the hand (0% persistency) at any time of evaluation following SCI (Fig. 1B). Urodynamic testing at 1 month showed a contractile bladder with low compliance and negative IWT. After 3 months, it was hypocontractile with normal bladder compliance and positive IWT. After 6 and 10 months, the bladder showed neurogenic detrusor overactivity with detrusor sphincter dyssynergia. 4. Discussion This is the first case report of a reappearance of SSR below lesion with pudendal nerve stimulation (i.e. stimulation below the lesion level) after 6 and 10 months following SCI, despite clinically- and electrophysiologically-proven sensory and motor complete SCI lesion. 4.1. SSR elicited by supraorbital nerve stimulation Appearance of the SSRs in SCI following supraorbital stimulation (SON) depends on the level of lesion. Our patient confirms previous observations in complete SCI patients with a neurological lesion level at T9, and showed that stimulation above the level of lesion evoked normal palmar SSRs, without any plantar SSRs, suggesting preserved sympathetic pathway function to the arm, but not to the leg. 4.2. SSR elicited by pudendal nerve stimulation below the lesion To our knowledge, this study showed for the first time reappearance and reproducibility of SSRs in humans below a complete SCI, elicited by pudendal nerve stimulation 6 and 10 months following a complete SCI, as was ascertained with clinical- and neurophysiological-examination (Fig. 1). When testing with SON stimulation the existence of palmar SSRs in combination with a lack of plantar SSRs indicates the complete lesion of efferent sympathetic pathways while testing with PN stimulation the existence of a plantar SSRs without palmar SSR suggests that spinal sympathetic pathways below the lesion were reactivated and after a latency of 6 months became excitable without supra-spinal sympathetic input. Reitz et al. (2002) have reported plantar SSRs with PN stimulation in seven complete SCI patients, while in other more recent studies, no more evidence was found to support their hypothesis that the spinal cord isolated from the brainstem could generate a SSR. The differences between earlier studies searching below level SSR (Cariga et al., 2002; Fuhrer, 1971; Prévinaire et al., 1993; Reitz et al., 2002), and our study, pertain 1. to methods of stimulation (stimulation parameters or site of stimulation), and 2. to observation of reproducibility during the time course following SCI. In earlier studies showing SSR below lesion level, unusually strong electrical stimulations were used (trains of ten 50 Hz-stimuli up to 80 mA; Reitz et al., 2002, or Fuhrer, 1971 used electrical stimuli with intensity “deemed the maximum permissible to avoid visible damage of the skin”). Similarly, bladder distension with a rise in intravesical pressure associated with bladder hyperreflexia induced SSR below the level of spinal lesion (Prévinaire et al., 1993). We report evaluation at different time points following SCI, from the very early through chronic phases, when strong electrical PN stimulation elicited perineal and plantar SSR, while the stimulus remained unnoticed by the subject, thus proving completeness of spinal lesion. With respect to the above discussion of differences in methods, we assume that stimulus characteristics are responsible for the presence of below level SSR, because these responses may be difficult to obtain, requiring strong stimuli as was suggested earlier (Reitz et al., 2002).
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Fig. 1. A). Three superimposed recordings of sympathetic skin response (SSR) elicited by the supraorbital nerve stimulation in the right hand, the feet and the perineum after 15 days and at 1, 3, 6 and 10 months following SCI. B). Three superimposed recordings of SSR elicited by the pudendal nerve stimulation in the right hand, the feet and the perineum after 15 days and at 1, 3, 6 and 10 months following SCI.
In complete SCI, below the lesion level almost all sympathetic reflexes disappear during a time period of several weeks termed “spinal shock”, most likely because descending activation of spinal networks and supraspinal control are interrupted (Janig, 1996). This phase is followed by somatic and autonomic spinal reorganization, allowing for recovery from symptoms such as orthostatic dysregulation. The simultaneous reappearance of the SSR and hyperactive detrusor, at 6 months following SCI, is well in line with cessation of spinal shock and stabilization of reflex activity in the cord below lesion, conjunct with clinical signs of spasticity (Hiersemenzel et al., 2000). Typically, reappearance
of tendon tap reflexes and muscle tone, or recovery of F wave and flexor reflex activity, is observed within 2 months (Hiersemenzel et al., 2000), together with clinical signs of spasticity, while reappearance of SSR and of detrusor overactivity in our patient occurred at 6 months, and is thus assumed in relation to overactivity in autonomic infra-lesional networks, including sympathetic pathways (Curt et al., 1997; Elliott and Krassioukov, 2006). The previous findings indicate that connections with supra-spinal structures are essential for evoking normal SSRs above the lesion (Cariga et al., 2002; Kumru et al., 2009; Nicotra et al., 2005a,b;
H. Kumru et al. / Autonomic Neuroscience: Basic and Clinical 181 (2014) 90–93
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Table 1 The mean latency and amplitude of sympathetic skin response (SSR) elicited by supraorbital and pudendal nerve stimulations in the right hand, the feet and the perineum. Sympathetic skin response elicited by supraorbital and pudendal nerve stimulations. Following SCI
15 days 1 month 3 months 6 months 10 months
Supraorbital nerve stimulation
Latency (ms) Amplitude (mV) Latency (ms) Amplitude (mV) Latency (ms) Amplitude (mV) Latency (ms) Amplitude (mV) Latency (ms) Amplitude (mV)
Pudendal nerve stimulation
Right hand
Right foot
Left foot
Perineum
Right hand
Right foot
Left foot
Perineum
1430 3.3 1480 2.2 1400 1.3 1370 3.2 1390 1.9
– 0 – 0 – 0 – 0 – 0
– 0 – 0 – 0 – 0 – 0
– 0 – 0 – 0 – 0 – 0
– 0 – 0 – 0 – 0 – 0
– 0 – 0 – 0 2058 1.3 2307 1.3
– 0 – 0 – 0 2160 0.5 2067 4
– 0 – 0 – 0 1825 0.06 2077 0.11
Previnaire et al., 2012). SSR elicited by PN stimulation in SCI patients depends on an intact sacral and lumbar spinal cord (Reitz et al., 2002). Clinical findings indicate that sudomotor neurons to the upper limb mainly pass through the spinal segments T1–T6 and to the lower limb through the segments until T10–T12 (Curt et al., 1996; Kumru et al., 2009; Reitz et al., 2002; Rodic et al., 2000). Reappearance of SSR in complete SCI below the lesion may be due to plastic changes in the spinal cord following injury. Central nervous system circuits undergo reorganization after lesions such as SCI (Raineteau and Schwab, 2001), occurring at multiple levels, including the spinal cord (Florence and Kaas, 1995). The functional reorganization is probably based on various mechanisms such as synaptic plasticity in pre-existing circuits and sprouting and anatomical reorganization that leads to the formation of new circuits (Florence and Kaas, 1995; Jain et al., 2000; Raineteau and Schwab, 2001). In this context, transmission can involve less efficient relays, resulting in perineal and plantar responses with altered latencies, as seen in our patient. In chronic SCI patients with lesion above T6, sympathetic overshoot activation may occur, due to disinhibition following disconnection from supraspinal centers, which leads to autonomic dysreflexia characterized by paroxysmal hypertensive episodes, combined with headache, profuse sweating, and concurrent bradycardia (Krassioukov et al., 2007). Curt et al (1997) reported that such autonomic failure can be expected when palmar SSR in high thoracic and cervical spinal injuries is lacking. Reappearance of SSR below lesion in our patient is unlikely to indicate that the supraspinal sympathetic control recuperates. A lack of other signs of sympathetic activation such as sweating, or signs of autonomic dysreflexia, is rather due to the low lesion level preserving splanchnic innervation under supra-spinal control. In summary, we found that the sympathetic skin response pathway, when elicited by pudendal nerve stimulation, is able to recuperate its reflex circuit below the lesion after 6 months following the isolation of the human caudal spinal cord. The recuperation of its reflex circuit seems time-dependent. Declaration of conflicting interests The authors declared no conflicts of interest with respect to the authorship and/or publication of this article. Funding This work was supported by the IFP (Internationale Stiftung für Forschung in Paraplegie Zürich) in co-funding of the EMSCI study group and in part by grants from Foundation La Marató TV3 PI110931 to HK and PI122830 and from the Instituto de Salud Carlos III PI10/ 00442 to JV.
References Abrams, P., Cardozo, L., Fall, M., Griffiths, D., Rosier, P., Ulmsten, U., Van Kerrebroeck, P., Victor, A., Wein, A., Standardisation Sub-Committee of the International Continence Society, 2003. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 61, 37–49. Cariga, P., Catley, M., Mathias, C.J., Savic, G., Frankel, H.L., Ellaway, P.H., 2002. Organisation of the sympathetic skin response in spinal cord injury. J. Neurol. Neurosurg. Psychiatry 72, 356–360. Chroni, E., Argyriou, A.A., Polychronopoulos, P., Sirrou, V., 2006. The effect of stimulation technique on sympathetic skin responses in healthy subjects. Clin. Auton. Res. 16, 396–400. Curt, A., Weinhardt, C., Dietz, V., 1996. Significance of sympathetic skin response in the assessment of autonomic failure in patients with spinal cord injury. J. Auton. Nerv. Syst. 61, 175–180. Curt, A., Nitsche, B., Rodic, B., Schurch, B., Dietz, V., 1997. Assessment of autonomic dysreflexia in patients with spinal cord injury. J. Neurol. Neurosurg. Psychiatry 62, 473–477. Elliott, S., Krassioukov, A., 2006. Malignant autonomic dysreflexia in spinal cord injured men. Spinal Cord 44, 386–392. Florence, S.L., Kaas, J.H., 1995. Large-scale reorganization at multiple levels of the somatosensory pathway follows therapeutic amputation of the hand in monkeys. J. Neurosci. 15, 8083–8095. Fuhrer, M.J., 1971. Skin conductance responses mediated by the transected human spinal cord. J. Appl. Physiol. 30, 663–669. Hiersemenzel, L.P., Curt, A., Dietz, V., 2000. From spinal shock to spasticity: neuronal adaptations to a spinal cord injury. Neurology 54, 1574–1582. Jain, N., Florence, S.L., Qi, H.X., Kaas, J.H., 2000. Growth of new brainstem connections in adult monkeys with massive sensory loss. Proc. Natl. Acad. Sci. U. S. A. 97, 5546–5550. Janig, W., 1996. Spinal cord reflex organization of sympathetic systems. In: Holstege, G., Bandler, R., Saper, C.B. (Eds.), Progress in Brain Research. Elsevier, Amsterdam, pp. 43–77. Korpelainen, J.T., Sotaniemi, K.A., Myllylä, V.V., 1993. Asymmetric sweating in stroke: a prospective quantitative study of patients with hemispheral brain infarction. Neurology 43, 1211–1214. Krassioukov, A.V., Karlsson, A.K., Wecht, J.M., Wuermser, L.A., Mathias, C.J., Marino, R.J., Joint Committee of American Spinal Injury Association and International Spinal Cord Society, 2007. Assessment of autonomic dysfunction following spinal cord injury: rationale for additions to International Standards for Neurological Assessment. J. Rehabil. Res. Dev. 44, 103–112. Kumru, H., Vidal, J., Perez, M., Schestatsky, P., Valls-Solé, J., 2009. Sympathetic skin responses evoked by different stimuli modalities in spinal cord injury patients. Neurorehabil. Neural Repair 23, 553–558. Nicotra, A., Young, T.M., Asahina, M., Mathias, C.J., 2005a. The effect of different physiological stimuli on skin vasomotor reflexes above and below the lesion in human chronic spinal cord injury. Neurorehabil. Neural Repair 19, 325–331. Nicotra, A., Catley, M., Ellaway, P.H., Mathias, C.J., 2005b. The ability of physiological stimuli to generate the sympathetic skin response in human chronic spinal cord injury. Restor. Neurol. Neurosci. 23, 331–339. Prévinaire, J.G., Soler, J.M., Hanson, P., 1993. Skin potential recordings during cystometry in spinal cord injured patients. Paraplegia 31, 13–21. Previnaire, J.G., Soler, J.M., Leclercq, V., Denys, P., 2012. Severity of autonomic dysfunction in patients with complete spinal cord injury. Clin. Auton. Res. 22, 9–15. Raineteau, O., Schwab, M.E., 2001. Plasticity of motor systems after incomplete spinal cord injury. Nat. Rev. Neurosci. 2, 263–273. Reitz, A., Schmid, D.M., Curt, A., Knapp, P.A., Schurch, B., 2002. Sympathetic sudomotor skin activity in human after complete spinal cord injury. Auton. Neurosci. 102 (1–2), 78–84. Rodic, B., Curt, A., Dietz, V., Schurch, B., 2000. Bladder neck incompetence in patients with spinal cord injury: significance of sympathetic skin response [see comments]. J. Urol. 163, 1223–1227. Veciana, M., Valls-Solé, J., Schestatsky, P., Montero, J., Casado, V., 2007. Abnormal sudomotor skin responses to temperature and pain stimuli in syringomyelia. J. Neurol. 254, 638–645. Vetrugno, R., Liguori, R., Cortelli, P., Montagna, P., 2003. Sympathetic skin response: basic mechanisms and clinical applications. Clin. Auton. Res. 13, 256–270.
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Short communication
Reappearance of sympathetic skin response below a thoracic level-9 complete spinal cord injury Hatice Kumru a,b,c,⁎, Martin Schubert d, Jesus Benito a,b,c, Eloy Opisso a,b,c, Joan Vidal a,b,c a
Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la UAB, 08916 Badalona, Barcelona, Spain Univ Autonoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Barcelona, Spain d Spinal Cord Injury Center, University Hospital Balgrist, Forchstrasse 340, 8008 Zurich, Switzerland b c
a r t i c l e
i n f o
Article history: Received 23 July 2013 Received in revised form 24 October 2013 Accepted 29 November 2013 Keywords: Sympathetic skin response Complete SCI Below lesion
a b s t r a c t Reappearance of sympathetic skin response (SSR) below lesion is reported in a patient with a complete thoracic-9 spinal cord injury 6 months following injury. SSR was elicited by electrical stimulation of supraorbital nerve (SON) and pudendal nerve (PN). SON stimulation induced SSRs only in the hand. SSRs were initially absent below the level of SCI but reappeared only with PN stimulation. This case suggests that 6 months following a complete lesion, the isolated spinal cord can generate a SSR. Possible underlying mechanisms and implications for autonomic plasticity below spinal lesion are discussed in view of the literature. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Sympathetic skin response (SSR) is a simple, non-invasive electrophysiological test that examines the common efferent pathways of the sympathetic nervous system (Veciana et al., 2007; Vetrugno et al., 2003). Centers of the cerebral cortex and the brainstem have been proposed as sites where sensory signals generate the SSR (Korpelainen et al., 1993; Vetrugno et al., 2003). The recording of SSR allows an independent and objective assessment of disconnection of the sympathetic spinal centers from supraspinal control, which has been related with autonomic dysfunction in lesion levels above T6 (Curt et al., 1997). Except in one study where reproducible SSRs had been shown below a complete SCI elicited by pudendal nerve stimulation (Reitz et al., 2002) in seven subjects, no further evidence was found to support the hypothesis that the spinal cord isolated from the brain stem could generate a SSR (Cariga et al., 2002; Kumru et al., 2009; Nicotra et al., 2005a,b; Previnaire et al., 2012). Here, we describe the reappearance and reproducibility of SSR below the spinal lesion level at different time points of neurophysiological evaluations, following SCI from subacute until chronic phase and its relation with detrusor overactivity. The case reported here was observed within a clinical trial: ‘Effectiveness of a treatment of neurogenic detrusor overactivity by application of early external pudendal nerve stimulation’ performed
⁎ Corresponding author at: Hospital de Neurorehabilitació Institut Guttmann, Camí Can Ruti s/n. Barcelona, 08916 Barcelona, Spain. Tel.: +34 93 497 77 00; fax: +34 93 497 77 15. E-mail address: [email protected] (H. Kumru). 1566-0702/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autneu.2013.11.003
within the European multi-center study about SCI (see www.emsci.org). SSR was repeatedly assessed to evaluate effects on autonomic neuroplasticity. 2. Methods A twenty-four-year-old male patient suffered a complete SCI, with a spinal cord transection, due to a traffic accident three days prior to admission at our institution. On admission, initial neurological examination revealed sensory and motor complete SCI at the thoracic (T) 9. 2.1. Neurophysiological studies We performed electrophysiological studies with the patient supine (with ambient temperature: 22–24°). Patient underwent a neurophysiological evaluation (see www.emsci.org) for motor evoked potentials (MEPs), somatosensory evoked potential (SSEP) recordings and SSR. A Medelec synergy electromyograph (Oxford Instruments, England) was used for all the tests. MEPs were elicited by single transcranial magnetic stimulus using a Magstim Super Rapid (Magstim Company, Whitland, UK) through a double-cone coil over the vertex. MEPs were recorded by surface electrodes over tibialis anterior and adductor hallucis muscles bilaterally. Single sweeps of 100 ms were recorded, filtered at 10–2000 Hz and amplified with a gain of 0.1 mV/div. For somato-sensory evoked potentials (SSEPs), the tibial nerve and the pudendal nerve (PN) were stimulated. For PN SSEPs, the stimulation was applied with ring electrode over penis (cathode on penis, anode
H. Kumru et al. / Autonomic Neuroscience: Basic and Clinical 181 (2014) 90–93
2–3 cm further distal) (with 100 mA intensity and 0.5 ms duration). Two sets of responses were averaged with sweeps of 100 ms, filters set at 10 and 2000 Hz, and amplified at a gain of 2 μV/div. MEPs and SSEPs were recorded after 15 days and after 1 year following SCI to verify completeness of injury of somatosensory afferents and efferents. SSRs were recorded on the right hand, the right and left feet, and the perineum. For the hand, the active electrode was attached to the palm and the reference electrode to the dorsum. For the foot, the active electrode was attached to the sole and the reference to the dorsum. For perineum recordings, the active electrode was attached to the perineum (below the scrotum) and the reference electrode to the iliac crest with the ground on the right leg. For all SSR recordings, we used a band-pass of 0.1 to 100 Hz and a sensitivity of 0.5 mV per division. Sweep duration was 10 s. For stimulation above SCI lesion level, electrical stimulus was applied to the right supraorbital nerve (SON), and below SCI lesion level the pudendal nerve (PN) was stimulated. Duration of electrical stimulus of SON was 0.5 ms and the intensity was set at 15 mA to induce a clear SSR. For PN stimulation, we used a ring electrode over the penis (cathode proximal, anode 2–3 cm distal) (with 100 mA intensity and 0.5ms duration). Each stimulus was repeated at least 3 times at each point with an interstimulus interval at least 30 s to reduce habituation (Chroni et al., 2006; Kumru et al., 2009). Urodynamic testing: Cystomanometry (CMG) and ice water test (IWT) were performed subsequently (Abrams et al., 2003). SSR and urodynamic recordings were obtained in independent sessions around 15 days (just SSRs) and 1, 3, 6 and 10 months following SCI. 2.2. Data analysis MEPs and SSEPs were evaluated visually at highest resolution, and latency and amplitude were calculated if there was any response. We calculated the onset latency of SSR in the hand, the feet and in the perineum. SSR was considered present if the amplitude of SSR was ≥50μV and amplitudes were determined peak to peak. If there was no identifiable SSR, response amplitude was considered “0” and no value was entered for response latency. The SSR probability (%) to the total number of stimuli (n = 3) was calculated for each stimulated nerve. We used one-way ANOVA to compare latencies of SSR in feet and perineum. 3. Results The patient completed neurophysiological studies without any complaints at all time points. He did not present any symptoms of autonomic dysreflexia such as sweating, change of skin color, or blood pressure, spontaneously or during any of the neurophysiological examinations. During PN stimulation, he did not report any sensation (complete SCI). The clinical diagnosis of complete SCI at T9 was confirmed one year following SCI, clinically and by neurophysiological evaluation. After 15 days and 1 year following SCI, MEPs were absent in the studied muscles on both sides and SSEPs also were absent with TN stimulation from both sides and with PN stimulation. Popliteal fossa potentials with TN stimulation were always normal. The SON stimulation induced SSRs only in the hand without any SSRs in the feet, or in the perineum, at any time of evaluation following SCI (Fig. 1A, Tables 1–2). PN stimulation did not induce SSRs in any of the recorded areas (right hand, feet and perineum) after 15 days, 1 and 3 months following SCI (Fig. 1B, Table 1). However, after 6 and 10 months following SCI, SSRs reappeared with PN stimulation in the feet and perineum, but not in the right hand (Table 1, Fig. 1B). The latencies of SSR in the feet and the perineum were not significantly different (p N 0.2).
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The SON stimulation induced SSRs in the hand with 100% persistency, without any SSRs in the feet, or in the perineum, at any time of evaluation following SCI (Fig. 1A). The PN stimulation induced SSRs in the feet and perineum with 100% of persistency after 6 months following SCI, but not in the hand (0% persistency) at any time of evaluation following SCI (Fig. 1B). Urodynamic testing at 1 month showed a contractile bladder with low compliance and negative IWT. After 3 months, it was hypocontractile with normal bladder compliance and positive IWT. After 6 and 10 months, the bladder showed neurogenic detrusor overactivity with detrusor sphincter dyssynergia. 4. Discussion This is the first case report of a reappearance of SSR below lesion with pudendal nerve stimulation (i.e. stimulation below the lesion level) after 6 and 10 months following SCI, despite clinically- and electrophysiologically-proven sensory and motor complete SCI lesion. 4.1. SSR elicited by supraorbital nerve stimulation Appearance of the SSRs in SCI following supraorbital stimulation (SON) depends on the level of lesion. Our patient confirms previous observations in complete SCI patients with a neurological lesion level at T9, and showed that stimulation above the level of lesion evoked normal palmar SSRs, without any plantar SSRs, suggesting preserved sympathetic pathway function to the arm, but not to the leg. 4.2. SSR elicited by pudendal nerve stimulation below the lesion To our knowledge, this study showed for the first time reappearance and reproducibility of SSRs in humans below a complete SCI, elicited by pudendal nerve stimulation 6 and 10 months following a complete SCI, as was ascertained with clinical- and neurophysiological-examination (Fig. 1). When testing with SON stimulation the existence of palmar SSRs in combination with a lack of plantar SSRs indicates the complete lesion of efferent sympathetic pathways while testing with PN stimulation the existence of a plantar SSRs without palmar SSR suggests that spinal sympathetic pathways below the lesion were reactivated and after a latency of 6 months became excitable without supra-spinal sympathetic input. Reitz et al. (2002) have reported plantar SSRs with PN stimulation in seven complete SCI patients, while in other more recent studies, no more evidence was found to support their hypothesis that the spinal cord isolated from the brainstem could generate a SSR. The differences between earlier studies searching below level SSR (Cariga et al., 2002; Fuhrer, 1971; Prévinaire et al., 1993; Reitz et al., 2002), and our study, pertain 1. to methods of stimulation (stimulation parameters or site of stimulation), and 2. to observation of reproducibility during the time course following SCI. In earlier studies showing SSR below lesion level, unusually strong electrical stimulations were used (trains of ten 50 Hz-stimuli up to 80 mA; Reitz et al., 2002, or Fuhrer, 1971 used electrical stimuli with intensity “deemed the maximum permissible to avoid visible damage of the skin”). Similarly, bladder distension with a rise in intravesical pressure associated with bladder hyperreflexia induced SSR below the level of spinal lesion (Prévinaire et al., 1993). We report evaluation at different time points following SCI, from the very early through chronic phases, when strong electrical PN stimulation elicited perineal and plantar SSR, while the stimulus remained unnoticed by the subject, thus proving completeness of spinal lesion. With respect to the above discussion of differences in methods, we assume that stimulus characteristics are responsible for the presence of below level SSR, because these responses may be difficult to obtain, requiring strong stimuli as was suggested earlier (Reitz et al., 2002).
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Fig. 1. A). Three superimposed recordings of sympathetic skin response (SSR) elicited by the supraorbital nerve stimulation in the right hand, the feet and the perineum after 15 days and at 1, 3, 6 and 10 months following SCI. B). Three superimposed recordings of SSR elicited by the pudendal nerve stimulation in the right hand, the feet and the perineum after 15 days and at 1, 3, 6 and 10 months following SCI.
In complete SCI, below the lesion level almost all sympathetic reflexes disappear during a time period of several weeks termed “spinal shock”, most likely because descending activation of spinal networks and supraspinal control are interrupted (Janig, 1996). This phase is followed by somatic and autonomic spinal reorganization, allowing for recovery from symptoms such as orthostatic dysregulation. The simultaneous reappearance of the SSR and hyperactive detrusor, at 6 months following SCI, is well in line with cessation of spinal shock and stabilization of reflex activity in the cord below lesion, conjunct with clinical signs of spasticity (Hiersemenzel et al., 2000). Typically, reappearance
of tendon tap reflexes and muscle tone, or recovery of F wave and flexor reflex activity, is observed within 2 months (Hiersemenzel et al., 2000), together with clinical signs of spasticity, while reappearance of SSR and of detrusor overactivity in our patient occurred at 6 months, and is thus assumed in relation to overactivity in autonomic infra-lesional networks, including sympathetic pathways (Curt et al., 1997; Elliott and Krassioukov, 2006). The previous findings indicate that connections with supra-spinal structures are essential for evoking normal SSRs above the lesion (Cariga et al., 2002; Kumru et al., 2009; Nicotra et al., 2005a,b;
H. Kumru et al. / Autonomic Neuroscience: Basic and Clinical 181 (2014) 90–93
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Table 1 The mean latency and amplitude of sympathetic skin response (SSR) elicited by supraorbital and pudendal nerve stimulations in the right hand, the feet and the perineum. Sympathetic skin response elicited by supraorbital and pudendal nerve stimulations. Following SCI
15 days 1 month 3 months 6 months 10 months
Supraorbital nerve stimulation
Latency (ms) Amplitude (mV) Latency (ms) Amplitude (mV) Latency (ms) Amplitude (mV) Latency (ms) Amplitude (mV) Latency (ms) Amplitude (mV)
Pudendal nerve stimulation
Right hand
Right foot
Left foot
Perineum
Right hand
Right foot
Left foot
Perineum
1430 3.3 1480 2.2 1400 1.3 1370 3.2 1390 1.9
– 0 – 0 – 0 – 0 – 0
– 0 – 0 – 0 – 0 – 0
– 0 – 0 – 0 – 0 – 0
– 0 – 0 – 0 – 0 – 0
– 0 – 0 – 0 2058 1.3 2307 1.3
– 0 – 0 – 0 2160 0.5 2067 4
– 0 – 0 – 0 1825 0.06 2077 0.11
Previnaire et al., 2012). SSR elicited by PN stimulation in SCI patients depends on an intact sacral and lumbar spinal cord (Reitz et al., 2002). Clinical findings indicate that sudomotor neurons to the upper limb mainly pass through the spinal segments T1–T6 and to the lower limb through the segments until T10–T12 (Curt et al., 1996; Kumru et al., 2009; Reitz et al., 2002; Rodic et al., 2000). Reappearance of SSR in complete SCI below the lesion may be due to plastic changes in the spinal cord following injury. Central nervous system circuits undergo reorganization after lesions such as SCI (Raineteau and Schwab, 2001), occurring at multiple levels, including the spinal cord (Florence and Kaas, 1995). The functional reorganization is probably based on various mechanisms such as synaptic plasticity in pre-existing circuits and sprouting and anatomical reorganization that leads to the formation of new circuits (Florence and Kaas, 1995; Jain et al., 2000; Raineteau and Schwab, 2001). In this context, transmission can involve less efficient relays, resulting in perineal and plantar responses with altered latencies, as seen in our patient. In chronic SCI patients with lesion above T6, sympathetic overshoot activation may occur, due to disinhibition following disconnection from supraspinal centers, which leads to autonomic dysreflexia characterized by paroxysmal hypertensive episodes, combined with headache, profuse sweating, and concurrent bradycardia (Krassioukov et al., 2007). Curt et al (1997) reported that such autonomic failure can be expected when palmar SSR in high thoracic and cervical spinal injuries is lacking. Reappearance of SSR below lesion in our patient is unlikely to indicate that the supraspinal sympathetic control recuperates. A lack of other signs of sympathetic activation such as sweating, or signs of autonomic dysreflexia, is rather due to the low lesion level preserving splanchnic innervation under supra-spinal control. In summary, we found that the sympathetic skin response pathway, when elicited by pudendal nerve stimulation, is able to recuperate its reflex circuit below the lesion after 6 months following the isolation of the human caudal spinal cord. The recuperation of its reflex circuit seems time-dependent. Declaration of conflicting interests The authors declared no conflicts of interest with respect to the authorship and/or publication of this article. Funding This work was supported by the IFP (Internationale Stiftung für Forschung in Paraplegie Zürich) in co-funding of the EMSCI study group and in part by grants from Foundation La Marató TV3 PI110931 to HK and PI122830 and from the Instituto de Salud Carlos III PI10/ 00442 to JV.
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